Study of Safety and Efficacy of Alpelisib With Everolimus or Alpelisib With Everolimus and Exemestane in Advanced Breast Cancer Patients, Renal Cell Cancer and Pancreatic Tumors

NCT02077933 | Completed Phase 1

• 2 other identifiers: CBYL719Z21022013-004829-86
• Study Type: interventional
• Target: 79
• Locations: 9 countries
• Sites: 22

Brief Summary

Dose escalation part: to determine the highest dose of alpelisib administered on a daily basis when given in combination with daily everolimus or in combination with daily everolimus and exemestane. Dose expansion part: To describe safety and tolerability of the alpelisib and everolimus or alpelisib, everolimus and exemestane combinations.

Conditions

Neoplasms; Breast Neoplasms; Kidney Neoplasms; Pancreatic Neuroendocine Neoplasms (pNETs)

Keywords

Solid tumors; renal cell carcinoma (RCC); pancreatic neuroendocrine tumors; breast cancer; PI3K inhibitor; BYL719; alpelisib; everolimus; exemestane

Outcome Measures

Primary Outcomes (2)

• Dose escalation : Incidence of dose Limiting Toxicity (DLTs)

  To determine the MTD and/or RDE of alpelisib in combination with everolimus, and the MTD and/or RDE of alpelisib in combination with everolimus and exemestane. A dose-limiting toxicity (DLT) is an adverse event or abnormal laboratory value assessed as being unrelated to disease, disease progression, inter-current illness, or concomitant medications, and that occurs within the first 35 days of treatment with alpelisib plus everolimus or alpelisib plus everolimus plus exemestane and meets any of the pre-defined criteria.

  First 35 days of treatment

• Dose expansion: Number of patients with adverse events as a measure of safety and tolerability

  Type, intensity, severity and seriousness of adverse events according to the National Cancer Institute Common Terminology Criteria for Advers Events (NCI CTC AE) v4.03. Dose interruptions, reductions and dose intensity

  Screening, every 28 days until 30 days after last dose

Secondary Outcomes (7)

• Dose escalation: Number of patients with adverse events as a measure of safety and tolerability

  Screening, every 28 days, until 30 days after last dose

• Dose escalation : alpelisib, everolimus and exemestane (when applicable) Plasma concentrations

  Cycle 1 Day 7, Cycle 1 Day 8, Cycle 1 Day 15, Cycle 1 Day 16, Cycle 1 Day 22, Cycle 2 Day 1, Cycle 2 Day 2, Cycle 2 Day 15, Day 1 of each subsequent cycle

• Dose escalation : alpelisib, everolimus drug-drug interaction

  Cycle 1 Day 7, Cycle 1 Day 8, Cycle 1 Day 15, Cycle 1 Day 16, Cycle 1 Day 22, Cycle 2 Day 1, Cycle 2 Day 2, Cycle 2 Day 15, Day 1 of each subsequent cycle

• Dose expansion: Progression free survival (Doublet cohorts)

  Baseline, every 8 weeks until first documented disease progression up to 2.5 years.

• Dose expansion : Duration of Response (Doublet and breast cancer cohorts)

  Baseline, every 8 weeks until first documented disease progressionup to 2.5 years.

Study Arms (3)

alpelisib and everolimus

EXPERIMENTAL

alpelisib and everolimus administered once a day

Drug: alpelisib; Drug: everolimus

alpelisib, everolimus and exemestane

EXPERIMENTAL

alpelisib, everolimus and exemestane administered once a day

Drug: alpelisib; Drug: everolimus; Drug: exemestane

alpelisib and exemestane

EXPERIMENTAL

alpelisib and exemestane administered once a day

Drug: alpelisib; Drug: exemestane

Interventions

alpelisib DRUG

alpelisib is administered orally once a day on a continuous dosing schedule and dosed on a flat-fixed dose and not adjusted by body weight or body surface area, starting on Day 8 of Cycle 1 in the dose escalation and Day 1 of Cycle 1 in the dose expansion. In the doublet dose escalation, the alpelisib starting dose is 300 mg. The alpelisib dose may be escalated or de-escalated, as needed. In the triplet dose escalation part, the alpelisib starting dose is one dose level lower of the MTD as determined during the doublet escalation. The alpelisib dose may be escalated or de-escalated, as needed. In the doublet dose expansion and triplet dose expansion (patients assigned to alpelisib, everolimus and exemestane), alpelisib is administered at the recommended dose determined in the dose escalation. In the triplet dose expansion (patients assigned to alpelisib and exemestane), alpelisib is administered at a dose of 250 mg daily.

alpelisib and everolimus; alpelisib and exemestane; alpelisib, everolimus and exemestane

everolimus DRUG

everolimus is administered orally once a day on a continuous dosing schedule and dosed on a flat-fixed dose and not adjusted by body weight or body surface area, starting on Day 1 of cycle 1 in both the dose escalation and dose expansion parts. In the dose escalation part, the everolimus starting dose is 2,5 mg. In the dose expansion part, everolimus is administered at the recommended dose determined in the dose escalation.

alpelisib and everolimus; alpelisib, everolimus and exemestane

exemestane DRUG

exemestane is administered orally once a day on a continuous dose of 25 mg starting on Day 1 of Cycle 1 in both the dose escalation and dose expansion.

alpelisib and exemestane; alpelisib, everolimus and exemestane

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult \> or = 18 years old
• has signed the Informed Consent Form
• has tumor tissue available for the analysis as described in the protocol
• has an Eastern Cooperative Oncology Group performance status ≤2
• has adequate bone marrow and organ function as defined in the protocol
• is able to swallow and retain oral medication
• has either measurable or non-measurable disease as per RECIST 1.1.
• \- all of above first 7 criteria plus has an histologically/cytologically confirmed pancreatic NeuroEndocrine Tumor as detailed in the protocol
• \- Patient randomized to the alpelisib and exemestane combination who has a radiologically documented progressive disease as detailed in the protocol

You may not qualify if:

• Patient has received previous treatment with a PI3K and/or AKT and/or mTOR inhibitor (mTOR inhibitor is allowed in expansion cohorts where patients should have areceived a prior mTOR inhibitor)
• Known intolerance or hypersensitivity to Everolimus or other rapamycin analogs
• Patient with primary central nervous system (CNS) tumor or CNS tumor involvement as detailed in the protocol
• Patient with diabetes mellitus, or documented steroid-induced diabetes mellitus
• Patient has a history of another malignancy within 2 years prior to starting study treatment as described in the protocol
• Patient who has not recovered to grade 1 or better (except alopecia) from related side effects of any prior antineoplastic therapy as detailed in the protocol
• Patient who has had systemic therapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to starting study treatment
• Patient who has received radiotherapy ≤ 4 weeks prior to starting study drugs, with exception of palliative radiotherapy (≤ 2 weeks prior to starting study drugs), who has not recovered from side effects of such therapy to baseline or Grade ≤ 1 and/or from whom ≥ 30% of the bone marrow was irradiated
• Patient who has undergone major surgery ≤ 4 weeks prior to starting study treatment or who has not recovered from side effects of such procedure
• Patient has a clinically significant cardiac disease or impaired cardiac function or any severe and/or uncontrolled medical conditions as detailed in the protocol
• Patient who is currently receiving medication with a known risk of prolonging the QT interval or inducing Torsades de Pointes (TdP) and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug treatment
• Patient who has participated in a prior investigational study within 30 days prior to enrollment as described in the protocol
• Patient who is currently receiving treatment with drugs known to be moderate or strong inhibitors or inducers of isoenzymes CYP34A or CYP2C8 as described in the protocol. Switching to a different medication prior to start of treatment is allowed
• Patient with impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral alpelisib, everolimus, exemestane
• Patient with known positive serology for human immunodeficiency virus

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (22)

Highlands Oncology Group

Fayetteville, Arkansas, 72703, United States

Location

Memorial Sloan Kettering Cancer Center SC - BYL719Z2102

New York, New York, 10065, United States

Location

Novartis Investigative Site

Bordeaux, 33075, France

Location

Novartis Investigative Site

Bordeaux, 33076, France

Location

Novartis Investigative Site

Paris, 75970, France

Location

Novartis Investigative Site

Villejuif, 94805, France

Location

Novartis Investigative Site

Berlin, 13353, Germany

Location

Novartis Investigative Site

Essen, 45136, Germany

Location

Novartis Investigative Site

Essen, 45147, Germany

Location

Novartis Investigative Site

Hanover, 30625, Germany

Location

Novartis Investigative Site

Hong Kong, Hong Kong

Location

Novartis Investigative Site

Budapest, H-1077, Hungary

Location

Novartis Investigative Site

Ancona, AN, 60126, Italy

Location

Novartis Investigative Site

Milan, MI, 20141, Italy

Location

Novartis Investigative Site

Modena, MO, 41124, Italy

Location

Novartis Investigative Site

Verona, VR, 37126, Italy

Location

Novartis Investigative Site

Amsterdam, 1066 CX, Netherlands

Location

Novartis Investigative Site

Utrecht, 3584CX, Netherlands

Location

Novartis Investigative Site

Barcelona, Catalonia, 08036, Spain

Location

Novartis Investigative Site

Madrid, 28009, Spain

Location

Novartis Investigative Site

Madrid, 28034, Spain

Location

Novartis Investigative Site

Manchester, M20 4BX, United Kingdom

Location

Related Publications (1)

• Fankhauser M, Bechmann N, Lauseker M, Goncalves J, Favier J, Klink B, William D, Gieldon L, Maurer J, Spottl G, Rank P, Knosel T, Orth M, Ziegler CG, Aristizabal Prada ET, Rubinstein G, Fassnacht M, Spitzweg C, Grossman AB, Pacak K, Beuschlein F, Bornstein SR, Eisenhofer G, Auernhammer CJ, Reincke M, Nolting S. Synergistic Highly Potent Targeted Drug Combinations in Different Pheochromocytoma Models Including Human Tumor Cultures. Endocrinology. 2019 Nov 1;160(11):2600-2617. doi: 10.1210/en.2019-00410.

  PMID: 31322702 DERIVED

Related Links

• Novartis Clinical Trial Results Database

MeSH Terms

Conditions

Neoplasms; Breast Neoplasms; Kidney Neoplasms; Carcinoma, Renal Cell

Interventions

Alpelisib; Everolimus; exemestane

Condition Hierarchy (Ancestors)

Neoplasms by Site; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Urologic Neoplasms; Urogenital Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 28, 2014
• First Posted: March 4, 2014
• Study Start: May 14, 2014
• Primary Completion: April 12, 2019
• Study Completion: April 12, 2019
• Last Updated: December 8, 2020

Record last verified: 2020-12

Data Sharing

• IPD Sharing: Will not share

Locations

ES (3); NL (2); US (2); HK (1); GB (1); DE (4); HU (1); FR (4); IT (4)